1. Field of the Invention
The present invention relates generally to the fields of genetic therapy. More particularly, it concerns administration of a herpes simplex viral vector to produce a therapeutic benefit in vascular and cardiovascular tissue. In additional aspects, the invention concerns combination therapies comprising administration of a herpes simplex viral vector and treatment with at least one additional pharmacological agent or surgical procedure, as well as use of surgical procedures and other targeting means to facilitate delivery of the herpes simplex virus vectors to vascular cells and tissues.
2. Related Technology
Vascular disease remains the leading cause of death and disability in the Western world [McGovern et al., New Engl. J. Med. 334:884-890, 1996]. Current treatment strategies are primarily aimed at risk factor modification and/or mechanical remediation of critical lesions. Although these strategies are often effective, the ability to genetically alter the basic pathophysiologic defects within diseased vascular tissue would offer a new paradigm of therapy and possibly revolutionize the treatment of vascular disease. The feasibility of vascular gene transfer was first demonstrated in 1989 when it was shown endothelial cells (EC's) expressing the retrovirally transduced lacZ gene could adhere and function in porcine iliac arteries [Nabel et al., Science 244:1342-1344, 1989]. Since then, nearly one billion U.S. dollars annually have been spent to refine and improve systems of transfer vectors and delivery systems [Svensson et al., Curr. Opin. Cardio. 13:369-374, 1998].
A variety of vectors have been used to transfer genes to vascular tissue, with variable results. Each of the most popular vector systems—naked plasmid DNA (Isner et al., Hum. Gene Ther. 7:989-1011, 1996; Baumgartner et al., Circ. 97:1114-1123, 1998], liposome-encapsulated DNA, [Armeanu et al., Mol. Ther. 1:366-375, 2000] retrovirus [Geary et al., Hum. Gene Ther. 5:1211-1216, 1994], adeno-associated virus (AAV) [Lynch et al., Circ. Res. 80:497-505, 1997], and adenovirus [Kay, J. Vasc. Surg. 24:160-161, 1996; Yeh et al., FASEB J. 11:615-623, 1997], have met with some success depending on the application. Efforts at gene transfer using only naked plasmid DNA have met with limited success due to low transfection efficiency [Baumgartner et al., Circ. 97:1114-1123, 1998; Reissen et al., Hum. Gene Ther. 4:449-458, 1993; Turunen et al., Gene Ther. 6:6-11, 1999]. DNA encapsulated within liposomes is somewhat more efficient [Armeanu et al., Mol. Ther. 1:366-375, 2000; Turunen et al., Gene Ther. 6:6-11, 1999; Takeshita et al., J. Clin. Invest. 93:652-661, 1994; Lim et al., Circ. 83:2007-2011, 1991; Matsumoto et al., J. Vasc. Surg. 27:135-144, 1998; Matsumura et al., J. Surg. Res. 85:339-345, 1999] but generally lacks complete penetrance with an intact basement membrane. Retrovirus was tested in early experiments [Nabel et al., Science 244:1342-1344, 1989; Dunn et al., Circ. 99:3199-3205, 1996], as well as more recently to transfer antisense oligonucleotides [Zhu et al., Circ. 96:628-635, 1997], but suffers greatly from its low efficiency in non-dividing cells. A relatively new vector system, adeno-associated virus (AAV), has been shown to efficiently infect skeletal muscle without inciting an intense immune response [Muzyczka, Curr. Topics Microbiol. Immunol. 158:97-129, 1992], and preliminary results have demonstrated that AAV is capable of transfecting vascular EC's [Lynch et al., Circ. Res. 80:497-505, 1997; Rolling et al., Gene Ther. 4:757-761, 1997; Kotin, Hum. Gene. Ther. 5:793-801, 1994; Xiao et al., J. Virol. 70:8098-8108, 1996] smooth muscle cells (SMC's, Rolling et al., Gene Ther. 4:757-761, 1997), and cardiocytes [Svensson et al., Circ. 99:201-205, 1999]. A recent report, however, indicates that gene transfer into vascular tissue with an intact endothelium may be problematic, with only 1-14% of cells staining positive after 30 days [Eslami et al., J. Vasc. Surg. 31:1149-1159, 2000].
Certainly, the most widely tested vector for vascular gene transfer has been replication-deficient adenovirus [Yeh et al., FASEB J. 11:615-623, 1997]. Adenoviral vectors exhibit a high penetrance in non-dividing cells, can be produced in high concentration, and can house relatively large transgenes. They have been used experimentally in vascular tissue to transfer a wide variety of marker and biologically active genes including Rb, [Chang et al., J. Clin. Invest. 95:2260-2268, 1995; Smith et al., Circ. 96:1899-1905, 1997] p21, [Chang et al., J. Clin. Invest. 95:2260-2268, 1995; Scheinman et al., J. Vasc. Surg. 29:360-369, 1999] cytosine deaminase [Harrell et al., 1997; Fortunato et al., 2000), C-type natriuretic peptide (Ueno et al., 1997), metalloproteinase inhibitors (Cheng et al., 1998; George et al., 2000; Dollery et al., 1999), hirudin, (Bishop et al., 1999) cyclooxygenase (Zoldhelyi et al., 1996), tissue factor pathway inhibitor (Zoldhelyi et al., 2000), thrombomodulin (Waugh et al., 2000), ecNOS (Varenne et al., 1998; Cable et al., 1999), βARKCT, (Fulton et al., 1996) and antisense RNA to bFGF (Hanna et al., 1997; Neschis et al., 1998; Hanna et al., 2000). The success of many of these protocols has been due, in part, to the very high concentration of vector used, as well as use of the popular model of creating injury by balloon inflation, which denudes endothelium and enhances vector penetration.
Gene transfer into intact vascular tissue, such as non-injured arteries or vein grafts, has proved more difficult (Eslami et al., 2000; Schwartz et al., 1999; Fulton et al., 1996; Hanna et al., 2000; Mann et al., 1995; Fulton et al., 1997; Fulton et al., 1998; Faries et al., 2000). Transfer efficiency is generally lower, the required doses are high, and the biologic effects less pronounced (Schwartz et al., 1999; Fulton et al., 1996; Hanna et al., 2000; Mann et al., 1995; Fulton et al., 1997; Fulton et al., 1998; Faires et al., 2000). Furthermore, and perhaps most importantly, an intact immune system remains a serious impediment to long-term transgene expression using adenovirus, as neutralization of the cytosolic episome generally is complete after the first week (Eslami et al., 2000; Chang et al., 1995). Immunomodulation of the host can extend the life of the transgene [Ascher et al., Ann. Vasc. Surg. 14:385-392, 2000], but global immunosuppression in the elderly population with vascular disease is clearly impractical. The problems inherent in adenoviral-based gene transfer in vascular tissue is best illustrated by the fact that, to date, only a single trial of therapeutic gene transfer has been reported [for angiogenesis, Rosengart et al., 1999], and there has yet to be a published clinical trial using adenoviral vectors for the treatment or prevention of vascular proliferative disorders.
A potential vector for the generation of long-term transgene expression is herpes simplex virus type one (HSV-1). HSV-1 is the virus that is responsible for recurrent oropharyngeal cold sores. It is a lytic, nonintegrating DNA virus that has demonstrated neurotropism and the establishment of long-term infections. Like adenovirus, HSV-1 can be manufactured in high titer and contains multiple non-essential genes that can potentially be deleted and replaced with large transgenes. This had led to speculation that the use of HSV may become a method for gene transfer for systemic disease (Culver, 1996; Lachmann and Efstathiou, 1997). However, the lytic and highly infectious nature of HSV, and the lifelong potential for latency, necessitate significant genetic modification prior to therapeutic use (Lachmann and Efstathiou, 1997; Huard et al., 1995; Advani et al., Gene Therapy 5:160-165, 1998]. The first set of recombinant herpesviruses to be generated lacked one or more genes (e.g., thymidine kinase or ribonucleotide reductase), which only moderately reduced viral growth in non-dividing cells (Martuza et al., 1991; Mineta et al., 1994; Miyatake et al., 1999). HSV-1 has been extensively studied as therapy for malignant tumors of the central nervous system using a variety of genetic manipulations [Advani et al., Gene Therapy 5:160-165, 1998; Chambers et al., 1995; Andreansky et al., Can. Res. 57:1502-1509, 1997]. More recently, attempts to render the virus nonvirulent have been made through deletion of both copies of the γ134.5 gene (Chou et al., 1990; Chou and Roizman, 1994).
However, the inventors are only aware of two phase I clinical trials using transfer vectors and delivery systems, both addressing the feasibility of transfer of angiogenic factors [Baumgartner et al., Circ. 1114-1123, 1998; Isner et al., 1995; Symes et al., 1999; Rosengart et al., 1999). Thus, despite the advances in the art, there is still a need for more effective vectors and methods of therapy for a wider application of somatic gene therapy to treat vascular disease.